Significant facilitation of metal-free aerobic oxidative cyclization of imines with water in synthesis of benzimidazoles

Article abstract of DOI:10.1016/j.tet.2014.12.043

A simple, convenient, and environmentally benign protocol for the synthesis of benzimidazoles from ortho-phenylenediamines and aldehydes via aerobic oxidation was developed in wet organic solvents. Notably, water significantly accelerated this transformation, which allowed us to achieve this important transformation without the assistance of any metal catalysts and other co-oxidants. Mechanistic studies suggested that water acts as the nucleophilic catalyst for this transformation by the conversion of disfavored 5-endo-trig cyclization of imines to favored 5-exo-tet cyclization via tetrahedral intermediates and the subsequent aerobic oxidation of the resulting benzimidazolines affords benzimidazoles.

Full text of DOI:10.1016/j.tet.2014.12.043

Accepted Manuscript
Significant facilitation of metal-free aerobic oxidative cyclization of imines with water in
synthesis of benzimidazoles
Ye-Sol Lee, Yeon-Ho Cho, SeungJae Lee, Jong-Kwan Bin, JoongHwan Yang,
GeeSung Chae, Cheol-Hong Cheon
PII:
S0040-4020(14)01747-5
10.1016/j.tet.2014.12.043
TET 26264
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 3 November 2014
Revised Date: 11 December 2014
Accepted Date: 12 December 2014
Please cite this article as: Lee Y-S, Cho Y-H, Lee S, Bin J-K, Yang J, Chae G, Cheon C-H, Significant
facilitation of metal-free aerobic oxidative cyclization of imines with water in synthesis of benzimidazoles,
Tetrahedron (2015), doi: 10.1016/j.tet.2014.12.043.
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Significant facilitation of metal-free aerobic
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Ye-Sol Lee, Yeon-Ho Cho, SeungJae Lee, Jong-Kwan Bin, JoongHwan Yang, GeeSung Chae, and Cheol-
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Hong Cheon*
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Department of chemistry, Korea university, Seoul 136701, Republic of Korea
LG Display R&D center, Paju-si, Gyeonggi-do 413779, Republic of Korea
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Significant facilitation of metal-free aerobic oxidative cyclization of imines with
water in synthesis of benzimidazoles
a
a
b
b
b
b
Ye-Sol Lee , Yeon-Ho Cho , SeungJae Lee , Jong-Kwan Bin , JoongHwan Yang , GeeSung Chae and
a,
Cheol-Hong Cheon ∗
a
Department of Chemistry, Korea University, Anam-ro, Seongbuk-gu, Seoul 136701, Republic of Korea
LG Display R&D Center, 245 LG-ro, Wollong-myeon, Paju-si, Gyeonggi-do 413779, Republic of Korea
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple, convenient, and environmentally benign protocol for the synthesis of benzimidazoles
from ortho-phenylenediamines and aldehydes via aerobic oxidation was developed in wet
organic solvents. Notably, water significantly accelerated this transformation, which allowed us
to achieve this important transformation without the assistance of any metal catalysts and other
co-oxidants. Mechanistic studies suggested that water acts as the nucleophilic catalyst for this
transformation by the conversion of disfavored 5-endo-trig cyclization of imines to favored 5-
exo-tet cyclization via tetrahedral intermediates and the subsequent aerobic oxidation of the
resulting benzimidazolines affords benzimidazoles.
Available online
Keywords:
Benzimidazole
Aerobic oxidation
Metal-free
2
009 Elsevier Ltd. All rights reserved.
Nucleophilic catalyst
Water
Baldwin’s rules
Introduction
have specified the reaction parameters required to control this
transformation. Herein, we report the synthesis of
benzimidazoles from ortho-phenylenediamines and aldehydes via
metal-free aerobic oxidation in wet organic solvents. Notably, we
for the first time elucidated the key controlling parameter in the
synthesis of benzimidazoles via metal-free aerobic oxidation;
water plays a crucial role in the synthesis of benzimidazoles
under aerobic oxidation conditions by converting the disfavored
Benzimidazoles are important building blocks found in
biologically and therapeutically active compounds, natural
products, and functional materials. Therefore, tremendous effort
1
has been made to develop efficient methods for the synthesis of
2,3
these compounds. One conventional method for the synthesis
of benzimidazoles involves the oxidative cyclization of imines
derived from ortho-phenylenediamines with aldehydes in the
presence of oxidants. However, many of these protocols produce
toxic and/or environmentally problematic by-products, which
often requires tedious workup and purification procedures.
5
-endo-trig cyclization of imines to the favored 5-exo-tet
4
cyclization through tetrahedral intermediates. This finding
enables us to synthesize benzimidazoles without using any metal
catalysts and/or co-oxidants.
Because molecular oxygen is an abundant, inexpensive and
environmentally benign oxidant, aerobic oxidations using
molecular oxygen as the terminal oxidant have attracted much
Results/Discussion
Our group has been interested in the development of new
protocols for the synthesis of biologically important
heteroaromatic compounds via metal-free aerobic oxidation
reactions in the presence of a nucleophile which could facilitate
this transformation by converting the less favored endo-
cyclization of imines to the more favored exo-cyclization through
tetrahedral intermediates generated by the addition of the
5
attention from the synthetic community as green protocols. In
this regard, a number of protocols for the synthesis of
benzimidazoles under aerobic oxidation conditions have been
6
developed. In contrast to the aerobic oxidation protocols for the
synthesis of other benzofused 1,3-azoles, such as benzoxazoles
and benzothiazoles, generally requiring transition metal
7,8
11-14
catalysts, there have been a few examples of the synthesis of
nucleophile to the imines.
For example, we recently
9,10
benzimidazoles via the metal-free aerobic oxidation protocols.
developed a highly efficient method for the synthesis of
benzoxazoles 1 from 2-aminophenol and aldehydes via metal-
free aerobic oxidation using cyanide as the nucleophilic catalyst.
However, none of these previous reports for the synthesis of
benzimidazoles under the metal-free aerobic oxidation conditions
—
——
∗
Corresponding author. Tel.: +82-2-3290-3147; fax: +82-2-3290-3121; e-mail: cheon@korea.ac.kr

2
Tetrahedron
It was found that cyanide significant
A
a
C
cce
C
le
E
ra
P
tedTEth
D
is MASc
NU
he
m
S
e
C
2
R
.
IP
Working hypothesis for the synthesis of
T
transformation by promoting the cyclization of an imine by
converting disfavored 5-endo-trig-cyclization of the imine into
favored 5-exo-tet-cyclization through tetrahedral intermediate A
benzimidazoles 5 via metal-free aerobic oxidation with a
different nucleophile.
11
(Scheme 1a).
To test this hypothesis, several nucleophiles were investigated
as catalysts for the synthesis of benzimidazoles under the similar
reaction conditions used for the benzoxazole synthesis (Table
When this protocol was attempted to be extended to the
synthesis of benzimidazoles with ortho-phenylenediamine and
aldehydes, the expected benzimidazoles were not obtained;
instead, 2-aminoquinoxalines 2 were obtained in good yields via
the 6-exo-dig cyclization at the carbon of the nitrile group in
11
1
). Delightfully, iodide was found to significantly accelerate this
transformation; benzimidazole 5a was obtained from ortho-
phenylenediamine 3a and benzaldehyde 4a in an excellent yield
13
tetrahedral intermediates B (Scheme 1b).
o
in the presence of a stoichiometric amount of iodide at 80 C
(
entry 2). However, 5a was not obtained in the absence of iodide,
a) Synthesis of benzoxazoles with cyanide
O
presumably because imine I could not undergo cyclization
through the disfavored 5-exo-trig cyclization (entry 1). When this
reaction was carried out under argon atmosphere, only a trace
amount of 5a was obtained, indicating that the molecular oxygen
present in air acts as the terminal oxidant in this transformation
OH
OH
O
N
H
R
NaCN
R
open flask
NH2
N
R
1
(
entry 3). Next, other nucleophiles were investigated as the
5
-endo-trig
NaCN
aerobic
oxidation
catalysts in this transformation. However, other nucleophiles did
not promote this transformation at all (entries 4 and 5). The
nucleophilicity of the halide turned out to slightly affect this
transformation; KCl and KBr also afforded the desired product in
high yields, but longer reaction times were needed with these less
nucleophilic halides than iodide (entries 6 and 7).
OH
5
-exo-tet
O
R
CN
R
N
H
N
H
A
b) Synthesis of 2-aminoquinoxalines with cyanide
O
Table 1. Optimization of Reaction Conditions
NH2
NH2
N
NH2
R
H
H
R
NaCN
NH2
O
Nu (x mol%)
N
+
Ph
open flask
NH2
N
R
N
o
H
Ph
4 A MS, solvent, 80 C
open flask
N
I
NH
2
2
3a
4a
5a
aerobic
NaCN
oxidation
[
a] Isolated yield of 5a.
H
H
N
N
NH2
N
NH2
R
[a]
5
-exo-tet
C
6-exo-dig
Entry
Nu (x mol%)
-
Solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
Time (h)
48
Yield (%)
R
N
H
N
H
R
[b]
N
H
1
2
3
4
5
6
7
8
9
1
1
N.R.
B
KI (100)
KI (100)
24
93
Scheme 1. Synthesis of heteroaromatic compounds via metal-
[c]
48
Trace
free aerobic oxidation in the presence of cyanide.
[
b]
NaOAc (100)
DMAP (100)
KCl (100)
KBr (100)
KI (100)
KI (100)
KI (100)
KI (100)
KI (10)
48
N.R.
N.R.
89
[
b]
Although the aerobic oxidation of ortho-phenylenediamines
and aldehydes in the presence of cyanide only afforded 2-
aminoquinoxalines, in which tetrahedral intermediates
underwent 6-exo-dig cyclization rather than 5-exo-tet cyclization,
we envisioned that the benzimidazoles could be intrinsically
synthesized with a different nucleophile (instead of cyanide)
under aerobic oxidation conditions, where tetrahedral
intermediates B’, generated by the addition of the nucleophile to
imines I, undergo only 5-exo-tet cyclization, not 6-exo-dig
cyclization (Scheme 2).
48
36
B
36
90
24
91
[
b]
CH
3
CN
24
N.R.
N.R.
N.R.
91
[b]
0
1
1,4-Dioxane
Toluene
DMF
24
[b]
24
O
H
NH2
NH2
NH2
N
12
13
48
N
4
R
Nu
H
R
R
open flask
N
KI (5)
DMF
96
84
I
5
3
1
4
KI (1)
DMF
120
50
5
-endo-trig
Nu
oxidation
[
[
b] N.R. means no reaction.
c] Under argon atmosphere.
H
N
NH
2
5
-exo-tet
Nu
R
R
No 6-exo-dig
N
H
Because previous studies on the metal-free aerobic oxidation
N
H
6
B'
protocols for the synthesis of benzimidazoles demonstrated that
9
these transformations could be performed in diverse solvents,

3
the effect of reaction media was further inve
A
stig
C
at
C
ed
E
(
P
en
T
tri
ED MANUSCRIPT
es
2
and 8-11). Rather unexpectedly, the choice of the solvent
significantly affected the efficiency of this transformation; the
desired product 5a was obtained in high yields in DMF and
DMSO (entries 2 and 8), whereas no reaction was observed in
any other solvent (entries 9-11). Because the reaction in DMF
afforded the desired product 5a in a slightly better yield than that
in DMSO, DMF was selected for further study.
Table 2. Effect of Additives on the Synthesis of Benzimidazoles
via Aerobic Oxidation
H
NH2
O
KI (x mol%)
N
+
Ph
o
H
Ph
Additive, DMF, 80 C
open flask
N
NH
2
3a
4a
5a
On the basis of the working hypothesis in conjugation with
our previous studies on the synthesis of benzoxazoles via aerobic
oxidation in the presence of a nucleophile, this transformation
was intrinsically possible with a catalytic amount of KI. Thus, we
investigated this transformation with a catalytic amount of KI
[a]
Entry
KI (x mol%)
Additive
4A MS
Time (h)
Yield (%)
1
2
3
4
100
100
-
24
12
12
2
93
91
54
94
-
(entries 2, 12-14). To our delight, a catalytic amount of KI was
-
sufficient enough to promote this transformation; even with 5
mol % of KI, the desired product was obtained in high yield,
albeit a long reaction time was needed.
[
b]
-
water
[
[
a] Isolated yield of 5a.
b] 10 vol % of water was used.
With these results in hand, we attempted to demonstrate the
advantages of the methods developed by our group in the
selective synthesis of either benzimidazoles
5
or 2-
On the basis of this interesting finding, the role of molecular
sieves, i.e., the role of water, was explored on this transformation
Table 2). It was found that molecular sieves were not actually
aminoquinoxalines 2 from the same substrate depending on the
choice of a nucleophilic reagent (Scheme 3). For example,
benzimidazole 5 was expected to be produced with KI as the
nucleophilic catalyst as shown in Scheme 3, while NaCN would
yield 2-aminoquinoxaline 2 under the similar reaction conditions.
(
needed in this transformation; the formation of 5a took place in
the absence of molecular sieves without any loss of efficiency
even in a short reaction time (entries 1 and 2). Surprisingly, this
reaction proceeded in the absence of KI and molecular sieves; the
desired product 5a was obtained in 54 % yield (entry 3).
Furthermore, water was found to significantly accelerate the
formation of 5a; when water was intentionally added to the
reaction mixture, this aerobic oxidation proceeded much faster to
yield 5a in an excellent yield and a much shorter reaction time
H
N
KI
R
O
aerobic
N
NH2
NH2
oxidation
H
R
NH2
5
4
N
R
3
N
N
NH2
I
NaCN
(entry 4).
aerobic
oxidation
R
2
With these unexpected results, we conducted a literature
survey on the synthesis of benzimidazoles via aerobic oxidation
and found that there have been a few reports of metal/additive-
free aerobic oxidation protocols for the synthesis of
Scheme 3. Diverse synthesis of 2-aminoquinoxalines 2 or
benzimidazoles 5 from the same substrates depending on the
choic of the nucleophile.
9
benzimidazoles. However, none of them clearly specified
whether their optimized reaction medium was completely
anhydrous. Since our result strongly suggested that water
significantly facilitate the formation of benzimidazoles under
When KI was used as a nucleophilic catalyst, as expected, the
corresponding benzimidazole 5a was obtained in an excellent
yield (Eq. 1). However, the reaction with NaCN furnished 2-
13
metal-free aerobic oxidation conditions, the effect of water on
this transformation in various aprotic organic solvents was
investigated (Table 3). As expected, water significantly
accelerated this transformation in various organic solvents; 5a
was obtained in good-to-excellent yields in any wet aprotic
solvent, while only a trace amount of 5a was obtained in a dry
solvent (entries 1-5).
aminoquinxoline
2
in low yield; rather unexpectedly,
benzimidazole 5a was obtained as the major product (Eq. 2).
H
NH2
KI (100 mol%)
N
O
Ph
( 1 )
+
+
Ph DMF, 80 oC, 24 h
open flask
H
H
N
NH2
4a
5a
3a
>
90 %
Table 3. Effect of water on the synthesis of benzimidazoles
NH2
NH2
N
NH
2
NaCN (110 mol%)
O
+
5a ( 2 )
Conditions A or B [a]
H
DMF, 80 oC, 8 h
open flask
NH2
N
N
Ph
N
Ph
O
~
70 %
Ph
+
3a
4a
2
NH2
H
Ph
open flask
~
10 %
3a
4a
5a
Because the formation of benzimidazole 5a has never been
[b]
Yield (%)
Method A Method B
achieved during our previous attempts in the synthesis of
13
benzimidazoles with NaCN, we carefully compared the reaction
conditions in Eq. 2 with those used previously for the synthesis
Entry
solvent
DMF
Time (h)
13
[c]
[d]
1
2
3
3
Trace
98 (91)
of 2-aminoquinoxaline, and found that molecular sieves were
not accidently added to the reaction mixture in Eq. 2. This result
strongly suggested that water play a crucial role in this
[
c]
DMSO
MeCN
8
Trace
Trace
85
15
transformation.
[c]
24
78

4
Tetrahedron
ACCEPTED MANUSCRIPT
[
c]
4
1,4-Dioxane
Toluene
24
24
Trace
Trace
67
[c]
5
69
Table 5. Substrate Scope
R2
o
R2
[
a] Conditions A: 4 Å MS, 80 C, open flask with a CaCl
2
tube. Conditions B:
R1
O
2
R1
NH
DMF/H O (9:1)
o
N
N
H
2
O (10 % (v)), 80 C, open flask without a CaCl
2
tube.
R3
1
+
R3
80 C, open flask
o
[
[
[
b] Determined by H NMR of the crude reaction mixture.
H
NH
2
3-24 h
c] Less than 5 % of yield of 5a.
3
4
5
d] The value in parentheses indicates the isolated yield of 5a.
1
2
3
6
[
Ent
5
R
R
R
C
Yield
(%)
a]
ry
Based on the result shown in Table 3, we expected that an
1
5a
5b
5c
5d
5e
5f
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Cl
CO
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Bn
Ph
H
5
91
87
91
93
92
92
82
95
96
90
96
94
90
93
93
69
69
70
70
83
86
80
82
90
90
96
alcoholic solvent might play a similar role as water in this
transformation; i.e., an alcoholic solvent would accelerate the
2
6
4-MeOC H4
1
6
transformation (Table 4). As expected, the aerobic oxidation
reaction took place in any alcoholic solvent in the absence of any
3
4-MeC
4-ClC
4-MeO
4-NO
2-MeOC
2-MeC
2-ClC
2-HOC
6 4
H
metal catalyst. However,
a significant amount of 1,2-
4
6 4
H
disubstituted benzimidazole 7a was obtained in an alcoholic
solvents including water and the amount of 7a decreases as the
alkyl group in the alcohol became bulkier (entries 1-4).
5
2 6 4
CC H
6
2 6 4
C H
7
5g
5h
5i
6 4
H
Table 4. Effect of Alcoholic Solvents on the Synthesis of
8
6 4
H
Benzimidazoles
Ph
Ph
H
N
NH2
solvent, 80 o
9
6 4
H
O
C
N
N
Ph +
+
open flask
10
5j
6 4
H
H
Ph
N
NH2
3a
4a
5a
7a
1
1
1
1
1
1
1
1
1
2
1
2
3
4
5
6
7
8
9
0
5k
5l
1-naphthyl
2-naphthyl
2-furyl
[a]
Entry
Solvent
Time (h)
Yield (%) (5a : 7a)
5m
5n
5o
5p
5q
5r
5s
1
2
3
4
H
2
O
6
6
6
6
30 : 32
36 : 30
57 : 20
67 : 13
2-thienyl
2-pyridyl
cinnamyl
n-hexyl
c-hexyl
t-butyl
MeOH
EtOH
i-PrOH
[
a] Isolated yield of 5a and 7a, respectively.
Next, the substrate scope of this transformation was
investigated in wet DMF (Table 5). Various aromatic aldehydes
were applicable to this protocol (entries 1-10). The electronic
natures of aromatic aldehydes had little influence on the
formation of benzimidazoles; the desired products were obtained
in high-to-excellent yields regardless of electronic natures of
aromatic aldehydes (entries 1-6). In addition, sterically congested
aldehydes bearing a substituent at the ortho-position were
amenable to this protocol, affording the desired benzimidazoles
without any loss of efficiency (entries 7-10) This protocol could
be extended to fused aromatic aldehydes, heteroaromatic
aldehydes, and α,β-unsaturated aldehydes (entries 11-16).
Furthermore, aliphatic aldehydes were also applicable to this
protocol. However, aliphatic aldehydes furnished the desired
benzimidazoles in slightly lower yields than aromatic ones
5t
H
21
5u
5v
5w
5x
7a
5y
C
C
C
C
C
C
6
6
6
6
6
6
H
H
H
H
H
H
5
5
5
5
5
5
2
2
2
2
2
3
4
5
2
H
26
[
a] Isolated yield.
(
entries 17-19). In addition, formaldehyde was applicable to this
protocol affording the parent benzimidazole in 83 % yield (entry
0). The substituents on the ortho-phenylenediamine moiety
With these results, we attempted to elucidate the reaction
mechanism, particularly the role of water (or KI) in this aerobic
oxidation protocol for the synthesis of benzimidazoles. As shown
in Scheme 2, the oxidative cyclization of ortho-
phenylenediamine 3 with aldehyde 4 is generally believed to
proceeds as follows: (1) the formation of imine I, (2) the
cyclization of the imine to form benzimidazoline 6, and (3) the
oxidation of 6 to afford 5. Similar to our previous studies on the
synthesis of benzoxazoles via aerobic oxidation using cyanide as
the catalyst, we believed that the cyclization step would be the
2
were also investigated. The substituents slightly affected this
transformation and the desired products were obtained in
excellent yields regardless of the electronic nature of ortho-
phenylenediamine moiety (entries 1 and 21-23). Moreover, N-
substituted ortho-phenylenediamines were applicable to this
protocol, affording 1,2-disubstituted benzimidazoles without any
loss of efficiency (entries 24-26).

5
rate-determining step for this transformatio
oxidation conditions, because the 5-endo-trig cyclization of I is a
disfavored transformation according to the Baldwin’s rules.
A
n
C
u
C
nd
E
er
P
a
T
er
E
ob
D
ic MAdi
N
sfa
U
vo
S
re
C
d
R
5-
I
endo-trig cyclization of I. However, when water
P
T
was added to the imine solution, the equilibrium could be shifted
from imine I to the starting diamine 3 and aldehyde 4 through
tetrahedral intermediate 9. During this equilibrium, intermediate
could undergo the favored 5-exo-tet cyclization to generate
benzimidazoline 6. Final oxidation of 6 yields compound 5
1
4
17
To test this idea, when imine I was subjected to the aerobic
oxidation conditions in the absence of any nucleophilic catalyst, I
remained intact and no formation of benzimidazole 5a was
observed even after a long reaction time (Eq. 3). However, when
KI was added to the above reaction mixture from Eq. 3, the
aerobic oxidative cyclization smoothly proceeded to afford 5a in
9
19
(pathway C).
NH
NH
- H O
NH
2
2
2
2
R
CHO (4)
18
OH
R
an excellent yield (Eq. 4). Moreover, when water (50 vol % of
+
H O
2
NH2
N
H
N
R
DMF) was added to the above reaction mixture from Eq. 3, 5a
was also obtained without any loss of efficiency (Eq. 5).
9
I
1
8
3
pathway C
5-exo-tet
H
pathway A
5-endo-trig
KI
NH2
N
N
DMSO-d6, 4A MS
0 oC, 24 h
Ph
(
3 )
8
N
H
N
H
N
Ph
NH2
5
a
[
O]
pathway B
-exo-tet
open flask
I
I
R
R
No Reaction
5
N
N
N
H
R
KI (100 mol%)
5
6
H
8
Reaction mixture
from Eq. ( 3 )
5
a
( 4 )
( 5 )
0 oC, 24 h
open flask
8
quantitative
Scheme 4. Proposed Reaction Mechanism
H O (50 vol%)
2
Reaction mixture
from Eq. ( 3 )
5
a
80 oC, 1 h
open flask
To further verify the validity of the proposed reaction
mechanism, the same reaction was carried out using an alcohol as
the nucleophilic catalyst. When 3a and 4a were subjected to the
reaction conditions in a mixture of DMF and 2-propanol (9:1),
initially all the starting materials were completely converted into
imine I and no formation of the desired product 5a was observed.
However, in the presence of alcohol, the initially formed imine
was gradually converted into the desired product leading to the
formation of the desired product 5a in 70 % yield after 24 h (Eq.
quantitative
Furthermore, when 3a and 4a were directly subjected to dry
reaction conditions with molecular sieves, the desired
benzimidazole 5a was not formed and imine I was obtained in
moderate yield (Eq. 6). However, when KI was added to the
above reaction mixture from Eq. 6, this aerobic oxidation
proceeded to completion affording the desired product 5a in
quantitative yield (Eq. 7). Furthermore, when 3a and 4a were
directly subjected to the reaction conditions in wet DMF, 3a and
9
). This result also implied that an alcohol could act as the
nucleophilic catalyst, which could facilitate the cyclization of
imine through a tetrahedral intermediate, even though an alcohol
was not as efficient as water.
4
a
were completely converted to the corresponding
benzimidazole 5a even in a short reaction time (Eq. 8).
DMF/IPA (9:1)
NH2
NH2
NH2
NH2
NH2
N
O
4A MS
O
DMSO-d6, 4A MS
0 oC, 24 h
+
(
9 )
+
( 6 )
100 oC, 1 h
H
Ph
8
NH2
N
Ph
H
Ph
Ph
open flask
I
open flask
3
a
4a
I
3
a
4a
quantitative
~
30 %
KI (100 mol%)
2
4 h
Reaction mixture
from Eq. ( 6 )
( 7 )
( 8 )
5
a
80 oC, 24 h
open flask
quantitative
H
N
Ph
NH2
+
N
O
DMF/H O (9:1)
2
5a
5a
70 %
8
0 oC, 1 h
open flask
H
Ph
NH2
quantitative
3
a
4
a
This proposed reaction mechanism also explained why the
reaction from imine I required a much larger amount of water (50
vol % of DMF) than the direct reaction of 3a and 4a (10 vol % of
DMF). Because I might be more stable than starting materials 3a
and 4a, a significantly large amount of water was needed to shift
the equilibrium from imine to the starting materials through
tetrahedral intermediate 9, which could be susceptible for the 5-
exo-tet cyclization to form intermediate 6.
Based on these experimental results along with our recent
report on the benzoxazole synthesis under the aerobic oxidation
conditions, a possible reaction mechanism was proposed
(Scheme 4). The cyclization of imine I might be the rate-
determining step and not take place without any assistance of a
nucleophile because the 5-endo-trig cyclization of I is a
disallowed transformation according to the Baldwin’s rules. Thus,
the desired benzimidazole 5 could not be formed in the absence
of a nucleophilic catalyst (pathway A). However, in the presence
of KI, tetrahedral intermediate 8, generated by adding iodide to I,
could undergo the favored 5-exo-tet cyclization to furnish
benzimidazoline 6. The subsequent aerobic oxidation of 6 affords
the desired benzimidazole 5 (pathway B). For the significant
acceleration by water, we believed that water would play a
similar role as KI under anhydrous conditions. In the absence of
water, I remained intact even after a long reaction time due to the
Conclusion
We developed a highly efficient and environmentally benign
protocol for the synthesis of benzimidazoles via metal-free
aerobic oxidation in wet organic solvents. Although a few reports
on the synthesis of benzimidazoles via metal/additive-free
aerobic oxidation have been reported, we, for the first time,

6
Tetrahedron
elucidated the key controlling parameter in
A
th
C
e
C
sy
E
n
P
th
T
esi
E
s
D
of MA2H
N
),
U
7.
S
36
C
(d
R
,
IP
J
= 8.0 Hz, 2H), 7.18 (dd, J = 5.8, 3.0 Hz, 2H), 2.38
T
o o
benzimidazoles through metal/additive-free aerobic oxidation;
water plays a crucial role in this aerobic oxidation reaction.
Furthermore, we further clarified the role of water (or KI) as the
nucleophilic catalyst, which could promote the cyclization of
imines through the conversion of disfavored 5-endo-trig
cyclization to favored 5-exo-tet cyclization via a tetrahedral
intermediate generated by the addition of the nucleophile to the
imine. Further explorations on the applications of this aerobic
oxidation protocol for benzimidazole synthesis are currently
underway in our laboratory.
(s, 3H). Mp 270-271 C (lit. 276 C).
20
2
-(4-Chlorophenyl)-1H-benzimidazole (5d). A yellow solid.
1
Yield: 213 mg (93 %). R = 0.4 (EtOAc:hexanes = 1:2). H NMR
f
(
300 MHz, DMSO-d , ppm) δ: 8.19 (d, J = 8.5 Hz, 2H), 7.64 (d,
6
o
J = 8.8 Hz, 2H), 7.21 (dd, J = 6.0, 3.0 Hz, 2H). Mp 299-301 C
o
(lit. 302 C).
2
1
2-(4-Methoxycarbonylphenyl)-1H-benzimidazole (5e). A yellow
solid. Yield: 232 mg (92 %). R = 0.3 (EtOAc:hexanes:CH Cl =
1:2:1). H NMR (300 MHz, DMSO-d , ppm) δ: 8.32 (d, J = 8.5
f
2
2
1
6
Hz, 2H), 8.13 (d, J = 8.5 Hz, 2H), 7.63 (dd, J = 5.8, 3.3 Hz, 2H),
o
7
.24 (dd, J = 6.0, 3.0 Hz, 2H), 3.90 (s, 3H). Mp 232-234 C (lit.
o
Experimental Section
220 C).
2
1
General. All reactions were carried out in oven-dried glassware
in an open flask unless otherwise noted. Except as otherwise
indicated, all reactions were magnetically stirred and monitored
by analytical thin layer chromatography (TLC) using pre-coated
silica gel glass plates (0.25 mm) with F254 indicator.
Visualization was accomplished by UV light (254 nm), with
2-(4-Nitrophenyl)-1H-benzimidazole (5f). A light gray solid.
Yield: 220 mg (92 %). R = 0.3 (EtOAc:hexanes:CH Cl = 1:2:1).
f
2
2
1
H NMR (300 MHz, DMSO-d , ppm) δ: 8.41 (s, 4H), 7.65 (dd, J
= 5.9, 3.2 Hz, 2H), 7.25 (dd, J = 6.0, 3.0 Hz, 2H). Mp over 300
6
o
o
C (lit. 315 C).
20
2
-(2-Methoxyphenyl)-1H-benzimidazole (5g). A light brown
solid. Yield: 184 mg (82 %). R = 0.3 (EtOAc:hexanes = 1:2). H
combination
of
potassium
permanganate
and/or
1
f
phosphomolybdic acid solution as an indicator. Flash column
chromatography was performed according to the method of Still
using silica gel 60 (230 – 400 mesh). Yields refer to
chromatographically and spectrographically pure compounds,
unless otherwise noted. Commercial grade reagents and solvents
were used without further purification. Liquid aldehydes were
freshly distilled under an atmosphere of dry argon, and solid
aldehydes were purified by flash chromatography on silica gel.
All the ortho-phenylenediamine derivatives were purchased from
commercial sources and used directly without further purification.
N-Methyl- and N-benzyl-1,2-phenylenediamines were prepared
NMR (300 MHz, DMSO-d , ppm) δ: 8.31 (d, J = 7.7 Hz, 1H),
6
7
1
.58 – 7.63 (m, 2H), 7.47 (t, J = 7.7 Hz, 1H), 7.24 (d, J = 8.2,
H), 7.16 – 7.20 (m, 2H), 7.11 (t, J = 7.7 Hz, 1H), 4.03 (s, 3H).
o
o
Mp 186-188 C (lit. 150-180 C).
20
2-(2-Methylphenyl)-1H-benzimidazole (5h). A yellow solid.
1
Yield: 199 mg (95 %). R = 0.3 (EtOAc:hexanes = 1:2). H NMR
f
(300 MHz, DMSO-d , ppm) δ: 7.73 (d, J = 6.6 Hz, 1H), 7.60 (br,
6
2H), 7.34 – 7.41 (m, 3H), 7.21 (dd, J = 5.8, 3.0 Hz, 2H), 2.61 (s,
o
o
3H). Mp 227-228 C (lit. 200-220 C).
22
18,19
2-(2-Chlorophenyl)-1H-benzimidazole (5i). A light brown solid.
by the literature procedures.
NMR spectra were recorded at
1
o
1
Yield: 219 mg (96 %). R = 0.3 (EtOAc:hexanes = 1:2). H NMR
f
2
4
5 C unless stated otherwise: H NMR spectra were recorded at
(
300 MHz, DMSO-d , ppm) δ: 7.89 – 7.92 (m, 1H), 7.60 – 7.67
6
00/300 MHz. Tetramethylsilane was used as internal standards
1
(m, 3H), 7.49 – 7.57 (m, 2H), 7.24 (dd, J = 5.9, 3.2 Hz, 2H). Mp
for H NMR (δ: 0.0 ppm). The proton spectra were reported as
follows δ (position of proton, multiplicity, coupling constant J,
number of protons). Multiplicities are indicated by s (singlet), d
o
o
2
37-238 C (lit. 235 C).
2
2
2
-(2-Hydroxylphenyl)-1H-benzimidazole (5j). A white solid.
1
(
(
doublet), t (triplet), q (quartet), p (quintet), h (septet), m
multiplet) and br (broad).
Yield: 189 mg (90 %). R = 0.5 (EtOAc:hexanes = 1:2). H NMR
f
(
300 MHz, DMSO-d , ppm) δ: 8.06 (d, J = 8.0 Hz, 1H), 7.67 (br,
6
2
7
H), 7.35 – 7.42 (m, 1H), 7.29 (dd, J = 6.0, 3.0 Hz, 2H), 6.99 –
o o
Synthesis of benzimidazoles via metal-free aerobic oxidation in
wet DMF (Table 5): To a solution of an ortho-phenylenediamine
derivative 3 (1.0 mmol; 1.0 equiv) and an aldehyde 4 (1.1 mmol;
.09 (m, 2H). Mp 244-246 C (lit. 242 C).
23
2
-(1-Naphthyl)-1H-benzimidazole (5k). A yellow solid. Yield:
1
1
.1 equiv) were dissolved in wet DMF (DMF 9.0 mL, H O 1.0
2
o
235 mg (96 %). R = 0.3 (EtOAc:hexanes = 1:3). H NMR (300
f
mL). The resulting reaction mixture was stirred at 80 C in an
open flask, and the reaction progress was monitored by TLC. On
the complete consumption of 3, the reaction mixture was cooled
to room temperature and concentrated under reduced pressure.
The crude product obtained was purified by column
chromatography on silica gel to afford the corresponding
benzimidazole 5.
MHz, DMSO-d , ppm) δ: 9.11 (d, J = 7.7 Hz, 1H), 8.10 (d, J =
6
8
=
.2 Hz, 1H), 8.00 – 8.06 (m, 2H), 7.60 – 7.72 (m, 5H), 7.26 (dd, J
5.9, 3.2 Hz, 2H). Mp 267-269 C (lit. 270 C).
o o
2
0
2
2
-(2-Naphthyl)-1H-benzimidazole (5l). A yellow solid. Yield:
1
30 mg (94 %). R = 0.4 (EtOAc:hexanes = 1:3). H NMR (300
f
MHz, DMSO-d , ppm) δ: 8.73 (s, 1H), 8.30 (d, J = 8.5 Hz, 1H),
6
8
4
.07 (d, J = 9.1 Hz, 1H), 7.97 – 8.04 (m, 2H), 7.58 – 7.62 (m,
H), 7.21 (dd, J = 5.9, 3.2 Hz, 2H). Mp 220-222 C (lit. 217 C).
2
0
o o
2
(
-Phenyl-1H-benzimidazole (5a). A white solid. Yield: 176 mg
1
91 %). R = 0.3 (EtOAc:hexanes = 1:2). H NMR (300 MHz,
f
2
0
2
1
-(Furan-2-yl)-1H-benzimidazole (5m). A brown solid. Yield:
DMSO-d , ppm) δ: 8.17 – 8.19 (m, 2H), 7.46 – 7.59 (m, 5H),
6
1
o
o
66 mg (90 %). R = 0.4 (MeOH:CH Cl = 1:20). H NMR (300
7
.19 (dd, J = 5.9, 3.2 Hz, 2H). Mp 297-299 C (lit. 293-296 C).
f
2
2
MHz, DMSO-d , ppm) δ: 7.94 (s, 1H), 7.55 (br, 2H), 7.16 – 7.23
6
20
2
-(4-Methoxyphenyl)-1H-benzimidazole (5b). A pale yellow
(
m, 3H), 6.73 (dd, J = 3.4, 1.8 Hz, 1H). Mp was not available due
o o
solid. Yield: 196 mg (87 %). R = 0.3 (EtOAc:hexanes:CH Cl =
f
2
2
to decomposition of 5m at 290 C (lit. 290 C).
1
1
:1:1). H NMR (300 MHz, DMSO-d , ppm) δ: 8.10 (d, J = 8.8
6
2
0
2
-(Thien-2-yl)-1H-benzimidazole (5n). A light yellow solid. 186
Hz, 2H), 7.54 (br, 2H), 7.15 (dd, J = 5.2, 3.2 Hz, 2H), 7.10 (d, J =
1
o
o
mg (93 %). R = 0.5 (MeOH:CH Cl = 1:20). H NMR (300 MHz,
8
.8 Hz, 2H), 3.83 (s, 3H). Mp 233-234 C (lit. 226 C).
f
2
2
DMSO-d , ppm) δ: 7.83 (d, J = 3.6 Hz, 1H), 7.73(d, J = 4.9 Hz,
6
2
0
o
2
-(4-Methylphenyl)-1H-benzimidazole (5c). A yellow solid.
1
H), 7.50 – 7.59 (m, 2H), 7.15 – 7.26 (m, 3H). Mp over 300 C
1
o
Yield: 190 mg (91 %). R = 0.3 (EtOAc:hexanes = 1:2). H NMR
f
(lit. 330 C).
(
300 MHz, DMSO-d , ppm) δ: 8.06 (d, J = 8.0 Hz, 2H), 7.57 (br,
6

7
2
3
2
1
-(Pyrid-2-yl)-1H-benzimidazole (5o). A yel
A
lo
C
w
C
so
E
lid
P
.
TED
ld: MANUSCRIPT
Y
ie
1
82 mg (93 %). R = 0.5 (MeOH:CH Cl = 1:20). H NMR (300
f
2
2
MHz, CDCl , ppm) δ: 10.55 (br, 1H), 8.65 (d, J = 4.7 Hz, 1H),
3
8
1
.44 (d, J = 8.0 Hz, 1H), 7.83 – 7.92 (m, 2H), 7.48 – 7.56 (m,
H), 7.30 – 7.42 (m, 3H). Mp 226-228 C (lit. 218 C).
Acknowledgements
o
o
This work was supported by a National Research Foundation of
Korea (NRF) grant funded by the Korean Government (NRF-
2013R1A1A1008434 and NRF-20100020209). C.-H.C. also
thanks for a financial support from an NRF grant funded by the
Korean Government (NRF-2014-011165, Center for New
Directions in Organic Synthesis).
23
2
1
-trans-Cinnamyl-1H-benzimidazole (5p). A yellow oil. Yield:
1
52 mg (69 %). R = 0.4 (EtOAc:hexanes = 1:2). H NMR (300
f
MHz, DMSO-d , ppm) δ: 7.54 - 7.73 (m, 4H), 7.39 - 7.50 (m,
6
3
H), 7.36 (d, J = 6.9 Hz, 1H), 7.11 - 7.27 (m, 3H). Mp 200-202
o
o
C (lit. 190-200 C).
2
4
2
(
-Hexyl-1H-benzimidazole (5q). A white solid. Yield: 140 mg
1
69 %). R = 0.4 (EtOAc:hexanes = 1:1). H NMR (300 MHz,
f
References
DMSO-d , ppm) δ: 12.14 (br, 1H), 7.34 - 7.60 (m, 2H), 7.09 (d, J
6
=
3.0 Hz, 2H), 2.78 (t, J = 7.4 Hz, 2H), 1.74 (br, 2H), 1.29 (br,
1
.
For reviews on benzimidazoles, see: (a) Singla, P.; Luxami,
V.; Paul, K. RSC Adv. 2014, 4, 12422; (b) Bansal, Y.;
Silakari, O. Bioorg. Med. Chem. 2012, 20, 6208.
o o
6
H), 0.85 (br, 3H). Mp 135-136 C (lit. 135 C).
25
2
-Cyclohexyl-1H-benzimidazole (5r). A white solid. Yield: 140
1
mg (70 %). R = 0.4 (EtOAc:hexanes = 1:3). H NMR (300 MHz,
f
2. Another conventional method for the synthesis of
benzimidazoles involves the amide formation between
ortho-phenylenediamines and carboxylic acids and their
derivatives, followed by the dehydration of the amides in the
presence of acid or microwave irradiation. For recent
examples, see: (a) Rambabu, D.; Murthi, P. R. K.; Dulla, B.;
Rao, M. V. B.; Pal, M. Synth. Commun. 2013, 43, 3083; (b)
Wen, X.; Bakali, J. E.; Deprez-Poulain, R.; Deprez, B.;
Tetrahedron Lett. 2012, 53, 2440; (c) Maras, N.; Kocevar,
M. Helv. Chim. Acta, 2011, 94, 1860; (d) Niknam, K.;
Fatehi-Raviz, A. J. Iran. Chem. Soc. 2007, 4, 438; (e) Wang,
R.; Lu, X.-X.; Yu, X.-Q.; Shi, L.; Sun, Y. J. Mol. Catal. A:
Chem. 2007, 266, 198; (f) Wang, Y.; Sarris, K.; Sauer, D.
R.; Djuric, S. W. Tetrahedron Lett. 2006, 47, 4823; (g)
Charton, J.; Girault-Mizzi, S.; Sergheraert, C. Chem. Pharm.
Bull. 2005, 53, 492.
DMSO-d , ppm) δ: 12.09 (br, 1H), 7.31 - 7.60 (m, 2H), 6.97 -
6
7
.22 (m, 2H), 2.83 (tt, J = 11.40, 3.57 Hz, 1H), 2.00 (d, J = 12.64
Hz, 2H), 1.75 - 1.86 (m, 2H), 1.74 - 1.18 (m, 6H). Mp 268-270
o
o
C (lit. 270-285 C).
3
b
2
-(t-Butyl)-1H-benzimidazole (5s). A brown solid. Yield: 122
1
mg (70 %). R = 0.3 (EtOAc:hexanes = 1:3). H NMR (300 MHz,
f
DMSO-d , ppm) δ: 12.06 (s, 1H), 7.51 (d, J = 6.9 Hz, 1H), 7.39
6
(
3
d, J = 7.1 Hz, 1H), 7.06 – 7.13 (m, 2H), 1.38 (s, 9H). Mp over
00 C (lit. 330 C).
o
o
2
6
Benzimidazole (5t). A white solid. Yield: 97.7 mg (83 %). R =
f
1
0
.5 (Acetone:MeOH = 30:1). H NMR (300 MHz, DMSO-d ,
6
ppm) δ: 12.44 (br, 1H), 8.20 (s, 1H), 7.46-7.70 (m, 2H), 7.18 (br,
o
o
1
H). ). Mp 178-180 C (lit. 171-173 C).
2
0
5
-Methyl-2-phenyl-1H-benzoimidazole (5u). A yellow solid.
1
Yield: 179 mg (86 %). R = 0.4 (EtOAc:hexanes = 1:3). H NMR
3. For the examples of transition-metal catalyzed synthesis of
benzimidazoles, see: (a) Kumar, R. K.; Punniyamurthy, T.
RSC Adv. 2012, 2, 4616; (b) Kim, Y.; Kumar, M. R.; Park,
N.; Heo, Y.; Lee, S. J. Org. Chem. 2011, 76, 9577; (c) Biju,
A. T.; Hirano, K.; Glorius, F. J. Org. Chem. 2009, 74, 9570.
f
(
300 MHz, DMSO-d , ppm) δ: 8.15 (d, J = 7.1 Hz, 2H), 7.44 -
6
7
.57 (m, 4H), 7.32 (br, 1H), 7.02 (d, J = 7.1 Hz, 1H), 2.43 (s, 3
o o
H). ). Mp 245-249 C (lit. 243 C).
2
0
5
-Chloro-2-phenyl-1H-benzoimidazole (5v).
A pink solid.
1
Yield: 183 mg (80 %). R = 0.4 (EtOAc:hexanes = 1:3). H NMR
4. For recent examples, see: (a) with IBD: Du, L.-H.; Wang,
f
(
300 MHz, DMSO-d , ppm) δ: 8.13 - 8.19 (m, 2H), 7.51 - 7.66
Y.-G.; Synthesis 2007, 5, 675; (b) with In(OTf) : Trivedi, R.;
De, S. K.; Gibbs, R. A. J. Mol. Catal. A: Chem. 2006, 245,
6
3
o
(m, 3H), 7.23 (dd, J = 8.7, 2.1 Hz, 1H). ). Mp 232-233 C (lit.
o
2
15 C).
8; (c) with I : Gogoi, P.; Konwar, D. Tetrahedron Lett. 2006,
2
2
7
47, 79; (d) with Yb(OTf) : Curini, M.; Epifano, F.;
3
2
-Phenyl-3H-benzoimidazole-5-carboxylic acid (5w). A yellow
Montanari, F.; Rosati, O.; Taccone, S. Synlett 2004, 1832;
(e) with DDQ: Eynde, J. J. V.; Delfosse, F.; Lor, P.;
Haverbeke, Y. V. Tetrahedron 1995, 51, 5813.
solid. Yield: 208 mg (82 %). R = 0.4 (EtOAc:hexanes:MeOH =
:5:1). H NMR (300 MHz, DMSO-d , ppm) δ: 8.20 (d, J = 6.9
Hz, 3H), 7.84 (d, J = 8.5 Hz, 1H), 7.51 - 7.67 (m, 4H). ). Mp over
f
1
6
6
o
o
3
00 C (lit. 325 C).
5. For reviews on aerobic oxidation in organic synthesis, see:
(a) Allen, S. E.; Walvoord, R. R.; Padilla-Salinas, R.;
Kozlowski, M. C. Chem. Rev. 2013, 113, 6234; (b) Shi, Z.;
Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012, 41,
25
1
-Methyl-2-phenyl-1H-benzoimidazole (5x). A yellow solid.
Yield: 188 mg (90 %). R = 0.3 (EtOAc:hexanes = 1:2). H NMR
300 MHz, DMSO-d , ppm) δ: 7.84 – 7.87(m, 2H), 7.68 (d, J =
.2 Hz, 1H), 7.57 – 7.63 (m, 4H), 7.22 – 7.33 (m, 2H), 3.88 (s,
o o
1
f
(
8
3
6
3
381; (c) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.;
Humphrey, G. R.; Leazer, J. L. Jr.; Linderman, R. J.; Lorenz,
K.; Manley, J.; Pearlman, B. A.; Wells, A.; Zaks, A.; Zhang,
T. Y. Green Chem. 2007, 9, 411.
H). ). Mp 96-98 C (lit. 95 C).
28
1
-Benzyl-2-phenyl-1H-benzoimidazole (7a). A yellow solid.
Yield: 256 mg (90 %). R = 0.4 (EtOAc:hexanes = 1:2). H NMR
300 MHz, DMSO-d , ppm) δ: 7.71 – 7.74 (m, 3H), 7.52 – 7.54
m, 3H), 7.45 – 7.48 (m, 1H), 7.21 – 7.31 (m, 5H), 6.98 (d, J =
1
f
6
.
Selected examples of the synthesis of benzimidazoles under
aerobic oxidation conditions in the presence of metal
catalysts and/or additives, see: (a) Qiu, D.; Wei, H.; Zhou,
L.; Zeng, Q. Appl. Organometal. Chem. 2014, 28, 109; (b)
Yu, J.; Xu, J.; Lu, M. Appl. Organometal. Chem. 2013, 27,
606; (c) Lei, M.; Ma, L.; Hu, L. Synth. Commun. 2012, 42,
2981; (d) Riadi, Y.; Mamouni, R.; Azzalou, R.; Haddad, M.
E.; Routier, S.; Gullaumet, G.; Lazar, S. Tetrahedron Lett.
2011, 52, 3492; (e) Mao, Z.; Wang, Z.; Li, J.; Song, X.; Luo,
(
(
7
6
o
o
.0 Hz, 2H), 5.59 (s, 2H). ). Mp 138-139 C (lit. 133 C).
29
1
(
(
3
2
,2-diphenyl-1H-benzoimidazole (5y). A white solid. Yield: mg
1
90 %). R = 0.35 (CH Cl :hexanes:MeOH = 8:1:1). H NMR
400 MHz, CDCl , ppm) δ: 7.71 – 7.74 (m, 3H), 7.52 – 7.54 (m,
H), 7.45 – 7.48 (m, 1H), 7.21 – 7.31 (m, 5H), 6.98 (d, J = 7.0 Hz,
f 2 2
3
o o
H), 5.59 (s, 2H). Mp 109-110 C (lit. 110 C).

8
Tetrahedron
.; MANUsee
Y. Synth. Commun. 2010, 40, 1963; (f) M
Tapaswi, P. K.; Butchere, R. J. Aust. J. Chem. 2009, 62, 140;
g) Chen, Y.-X.; Qian, L.-F.; Zhang, W.; Han, B. Angew.
A
uk
C
ho
C
pa
E
d
P
hy
T
ay
E
, C
D
S
:
C
K
R
im
I
,
P
N. Y.; Cheon, C.-H. Tetrahedron Lett. 2014, 55,
T
2340.
(
1
1
6. For the metal/additive-free synthesis of benzimidazoles via
aerobic oxidation in alcoholic solvents. See ref 9a).
Chem., Int. Ed. 2008, 47, 9330; (h) Mukhopadhyay, C.;
Tapaswi, P. K. Tetrahedron Lett. 2008, 49, 6237.
7. Imine I was prepared in ethanol under argon atmosphere at
7
.
For examples of the synthesis of benzoxazoles via aerobic
oxidation, see: (a) Yoo, W.-J.; Yuan, H.; Miyamura, H.;
Kobayashi, S. Adv. Synth. Catal. 2011, 353, 3085; (b) Chen,
W.-H.; Pang, Y. Tetrahedron Lett. 2009, 50, 6680; (c)
Kawashita, Y.; Nakamichi, N.; Kawabata, H.; Hayashi, M.
Org. Lett. 2003, 5, 3713; (d) Speier, G. J. Mol. Catal. 1987,
o
8
0 C. When the same reaction was performed under air
atmosphere, 5a and 7a were obtained.
18. Ebenezer, W. J.; Hutchings, M. G.; Jones, K.; Lambert, D.
A.; Watt, I. Tetrahedron Lett. 2007, 48, 1641.
1
2
2
2
2
2
9. Chattopadhyay, P.; Rai, R.; Pandey, P. S. Synth. Commun.
006, 36, 1857.
4
1, 253; (e) See ref 6(f).
2
8
9
.
.
For examples of the synthesis of benzothiazoles via aerobic
oxidation, see: (a) Parikh, N.; Kumar, D.; Roy, S. R.;
Chakraborti, A. K. Chem. Commun. 2011, 1797; (b) see also
refs 6(f) and 7(b).
0. Chen, C.; Chen, C.; Li, B.; Tao, J.; Peng, J. Molecules 2012,
7, 12506.
1
1. Kazerouni, M. R.; Bamoniri, A.; Mirjalili, B. F. Chem.
Heterocyclic Compd. 2014, 50, 35.
(a) Chen, G.-F.; Shen, H.-D.; Jia, H.-M.; Zhang, L.-Y.; Kang,
H.-Y.; Qi, Q.-Q.; Chen, B.-H.; Cao, J.-L.; Li, J.-T. Aust. J.
Chem. 2013, 66, 262; (b) Zhang, C.; Zhang, L.; Jiao, N.
Green Chem. 2012, 14, 3273; (c) Bachhav, H. M.; Bhagat, S.
B.; Telvekar, V. N. Tetrahedron Lett. 2011, 52, 5697; (d)
Panda, S. S.; Jain, S. C. Synth. Commun. 2011, 41, 729; (e)
Lin, S.; Yang, L. Tetrahedron Lett. 2005, 46, 4315.
2. Tushar, M.; Dhimant, K.; Kapse, G. K.; Hugar, M. H. J.
Appl. Chem. 2013, 2, 50.
3. Li, G.; Wang, J.; Yuan, B.; Zhang, D.; Lin, Z.; Li, P.; Huang,
H. Tetrahedron Lett. 2013, 54, 6934.
4. Weires, N. A.; Boster, J.; Magolan, J. Eur. J. Org. Chem.
2
012, 6508.
1
0. For the synthesis of benzimidazoles via metal-free aerobic
oxidation under visible light irradiation, see: (a) Park, S.;
Jung, J.; Cho, E. J. Eur. J. Chem. 2014, 4148. (b) Samanta,
S.; Das, S.; Biswas, P. J. Org. Chem. 2013, 78, 11184.
2
2
5. Xue, D.; Long, Y.-Q. J. Org. Chem. 2014, 79, 4727.
6. Graham, T. H.; Lin, W.; Shen, D.-M. Org. Lett. 2011, 13,
6
232.
1
1
1
1. For benzoxazoles, see: Cho, Y.-H.; Lee, C.-Y.; Ha, D.-C.;
2
2
2
7. Shargi, H.; Aberi, M.; Doroodmand, M. M. J. Iran Chem.
Soc. 2012, 9, 189.
Cheon, C.-H. Adv. Synth. Catal. 2012, 354, 2992.
2. For benzothiazoles, see: Cho, Y.-H.; Lee, C.-Y.; Cheon, C.-
8. Shelkar, R.; Sarode, S.; Nagarkar, J. Tetrahedron Lett. 2013,
H. Tetrahedron 2013, 69, 6565.
5
4, 6986.
3. For 2-aminoquinoxalines, see: Cho, Y.-H.; Kim, K.-H.;
9. Peng, J.; Ye, M.; Zong, C.; Hu, F.; Feng, L.; Wang, Y.;
Cheon, C.-H. J. Org. Chem. 2014, 79, 901.
Chen, W. J. Org. Chem. 2011, 76, 716.
1
1
4. Johnson, C. D. Acc. Chem. Res. 1993, 26, 476.
5. For the similar reactivity enhancement with water in metal-
free aerobic oxidation in the synthesis of quinazolinones,
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ACCEPTED MANUSCRIPT
Significant facilitation of metal-free aerobic
oxidative cyclization of imines with water in
synthesis of benzimidazoles
a
a
b
b
b
b
Ye-Sol Lee, Yeon-Ho Cho, SeungJae Lee, Jong-Kwan Bin, JoongHwan Yang, GeeSung Chae,
a,
and Cheol-Hong Cheon *
a
Department of Chemistry, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 136713, Republic of
Korea
b
LG Display R&D Center, 245 LG-ro, Wollong-myeon, Paju-si, Gyeonggi-do 413779, Republic of
Korea
Table of Contents
1
. General methods------------------------------------------------------------------------------------------------S2
Synthesis of benzimidazoles 5 via metal-free aerobic oxidation in the presence of a
2
.
nucleophile-------------------------------------------------------------------------------------------------S3
1
3
.
H NMR spectra of benzimidazoles 5-----------------------------------------------------------------S14
4
. References------------------------------------------------------------------------------------------------------S26
S1

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1
. General methods
All reactions were carried out in oven-dried glassware under air atmosphere unless otherwise
noted. Except as otherwise indicated, all reactions were magnetically stirred and monitored
by analytical thin layer chromatography (TLC) using pre-coated silica gel glass plates (0.25
mm) with F254 indicator. Visualization was accomplished by UV light (254 nm), with
combination of phosphomolybdic acid solution as an indicator. Flash column
chromatography was performed according to the method of Still using silica gel 60 (230 –
4
00 mesh). Yields refer to chromatographically and spectroscopically pure compounds,
unless otherwise noted.
Commercial grade reagents and solvents were used without further purification. Liquid
aldehydes were freshly distilled under an atmosphere of dry argon, and solid aldehydes were
purified by flash chromatography on silica gel. All the ortho-phenylenediamine derivatives
were purchased from commercial sources and used directly without further purification. N-
Methyl- and N-benzyl-1,2-phenylenediamines were prepared by the literature procedures,
1
,2
respectively.
1
H spectra were recorded on Varian Gemini 300 (300 MHz) NMR and Varian Gemini 400
(
400 MHz), respectively. Tetramethylsilane (TMS) (δ: 0.00 ppm) and DMSO-d (δ: 2.50
6
1
ppm) were used as internal standards for H NMR, respectively. The proton spectra were
reported as follows δ (position of proton, multiplicity, coupling constant J, number of
protons) and the carbon spectra were reported only δ (position of carbon). Multiplicities are
indicated by s (singlet), d (doublet), t (triplet), q (quartet), p (quintet), h (heptet), m
(multiplet) and br (broad).
S2

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2
. Synthesis of benzimidazoles 5 via metal-free aerobic oxidation in the
presence of a nucleophile
Conditions A: Synthesis of benzimidazoles via metal-free aerobic oxidation in
wet DMF:
R2
R2
R1
H O (10% vol.)
DMF, 80 C
2
R1
NH
O
o
N
N
R3
+
H
R3
open flask
3-24h
NH2
3
4
5
To a solution of a ortho-Phenylenediamine derivative 3 (1.0 mmol; 1.0 equiv) and an
aldehyde 4 (1.1 mmol; 1.1 equiv) were dissolved in wet DMF (DMF 9.0 mL, H O 1.0 mL).
2
o
The resulting reaction mixture was stirred at 80 C in an open flask, and the reaction progress
was monitored by TLC. On the complete consumption of 3, the reaction mixture was cooled
to room temperature and concentrated under reduced pressure. The crude product obtained
was purified by column chromatography on silica gel to afford the corresponding
benzimidazole 5.
Conditions B: Synthesis of benzimidazoles via metal-free aerobic oxidation in the
presence of KI:
H
NH2
O
N
KI (100 mol%)
+
R
o
H
R
4 A MS, DMF, 80 C
open flask
N
NH
2
3a
4
5
To a solution of a ortho-phenylenediamine derivative 3 (1.0 mmol, 1.0 equiv) and an
aldehyde 4 (1.1 mmol, 1.1 equiv) in DMF were added 4Å molecular sieve and KI (1.0 mmol,
o
1
.0 equiv). The resulting reaction mixture was stirred at 80 C in an open flask, and the
reaction progress was monitored by TLC. On the complete consumption of 3, the reaction
S3

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mixture was cooled to room temperature and concentrated under reduced pressure. The crude
product obtained was purified by column chromatography on silica gel to afford the
corresponding benzimidazole 5.
2
-1. Substrate scope for benzimidazoles 5 in wet DMF (Table 5)
3
2
-Phenyl-1H-benzimidazole (5a)
The spectroscopic data were in good agreement with the literature. A white solid. Yield: 176
1
mg (91 %). R = 0.3 (EtOAc:hexanes = 1:2). H NMR (300 MHz, DMSO-d , ppm) δ: 8.17 –
f
6
8
.19 (m, 2H), 7.46 – 7.59 (m, 5H), 7.19 (dd, J = 5.9, 3.2 Hz, 2H).
3
2
-(4-Methoxyphenyl)-1H-benzimidazole (5b)
The spectroscopic data were in good agreement with the literature. A pale yellow solid. Yield:
1
1
96 mg (87 %). R = 0.3 (EtOAc:hexanes:CH Cl = 1:1:1). H NMR (300 MHz, DMSO-d ,
f
2
2
6
ppm) δ: 8.10 (d, J = 8.8 Hz, 2H), 7.54 (br, 2H), 7.15 (dd, J = 5.2, 3.2 Hz, 2H), 7.10 (d, J = 8.8
Hz, 2H), 3.83 (s, 3H).
3
2
-(4-Methylphenyl)-1H-benzimidazole (5c)
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The spectroscopic data were in good agreement with the literature. A yellow solid. Yield: 190
1
mg (91 %). R = 0.3 (EtOAc:hexanes = 1:2). H NMR (300 MHz, DMSO-d , ppm) δ: 8.06 (d,
f
6
J = 8.0 Hz, 2H), 7.57 (br, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.18 (dd, J = 5.8, 3.0 Hz, 2H), 2.38 (s,
3
H).
3
2
-(4-Chlorophenyl)-1H-benzimidazole (5d)
The spectroscopic data were in good agreement with the literature. A yellow solid. Yield: 213
1
mg (93 %). R = 0.4 (EtOAc:hexanes = 1:2). H NMR (300 MHz, DMSO-d , ppm) δ: 8.19 (d,
f
6
J = 8.5 Hz, 2H), 7.64 (d, J = 8.8 Hz, 2H), 7.21 (dd, J = 6.0, 3.0 Hz, 2H)
4
2
-(4-Methoxycarbonylphenyl)-1H-benzimidazole (5e)
The spectroscopic data were in good agreement with the literature. A yellow solid. Yield: 232
1
mg (92 %). R = 0.3 (EtOAc:hexanes:CH Cl = 1:2:1). H NMR (300 MHz, DMSO-d , ppm)
f
2
2
6
δ: 8.32 (d, J = 8.5 Hz, 2H), 8.13 (d, J = 8.5 Hz, 2H), 7.63 (dd, J = 5.8, 3.3 Hz, 2H), 7.24 (dd,
J = 6.0, 3.0 Hz, 2H), 3.90 (s, 3H).
4
2
-(4-Nitrophenyl)-1H-benzimidazole (5f)
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The spectroscopic data were in good agreement with the literature. A light gray solid. Yield:
1
2
20 mg (92 %). R = 0.3 (EtOAc:hexanes:CH Cl = 1:2:1). H NMR (300 MHz, DMSO-d ,
f
2
2
6
ppm) δ: 8.41 (s, 4H), 7.65 (dd, J = 5.9, 3.2 Hz, 2H), 7.25 (dd, J = 6.0, 3.0 Hz, 2H).
3
2
-(2-Methoxyphenyl)-1H-benzimidazole (5g)
The spectroscopic data were in good agreement with the literature. A light brown solid. Yield:
1
1
8
7
84 mg (82 %). R = 0.3 (EtOAc:hexanes = 1:2). H NMR (300 MHz, DMSO-d , ppm) δ:
f
6
.31 (d, J = 7.7 Hz, 1H), 7.58 – 7.63 (m, 2H), 7.47 (t, J = 7.7 Hz, 1H), 7.24 (d, J = 8.2, 1H),
.16 – 7.20 (m, 2H), 7.11 (t, J = 7.7 Hz, 1H), 4.03 (s, 3H).
3
2
-(2-Methylphenyl)-1H-benzimidazole (5h)
The spectroscopic data were in good agreement with the literature. A yellow solid. Yield: 199
1
mg (95 %). R = 0.3 (EtOAc:hexanes = 1:2). H NMR (300 MHz, DMSO-d , ppm) δ: 7.73 (d,
f
6
J = 6.6 Hz, 1H), 7.60 (br, 2H), 7.34 – 7.41 (m, 3H), 7.21 (dd, J = 5.8, 3.0 Hz, 2H), 2.61 (s,
H).
3
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5
2
-(2-Chlorophenyl)-1H-benzimidazole (5i)
The spectroscopic data were in good agreement with the literature. A light brown solid. Yield:
1
2
19 mg (96 %). R = 0.3 (EtOAc:hexanes = 1:2). H NMR (300 MHz, DMSO-d , ppm) δ:
f
6
7
.89 – 7.92 (m, 1H), 7.60 – 7.67 (m, 3H), 7.49 – 7.57 (m, 2H), 7.24 (dd, J = 5.9, 3.2 Hz, 2H).
5
2
-(2-Hydroxylphenyl)-1H-benzimidazole (5j)
The spectroscopic data were in good agreement with the literature. A white solid. Yield: 189
1
mg (90 %). R = 0.5 (EtOAc:hexanes = 1:2). H NMR (300 MHz, DMSO-d , ppm) δ: 8.06 (d,
f
6
J = 8.0 Hz, 1H), 7.67 (br, 2H), 7.35 – 7.42 (m, 1H), 7.29 (dd, J = 6.0, 3.0 Hz, 2H), 6.99 –
7
.09 (m, 2H).
6
2
-(1-Naphthyl)-1H-benzimidazole (5k)
The spectroscopic data were in good agreement with the literature. A yellow solid. Yield: 235
1
mg (96 %). R = 0.3 (EtOAc:hexanes = 1:3). H NMR (300 MHz, DMSO-d , ppm) δ: 9.11 (d,
f
6
J = 7.7 Hz, 1H), 8.10 (d, J = 8.2 Hz, 1H), 8.00 – 8.06 (m, 2H), 7.60 – 7.72 (m, 5H), 7.26 (dd,
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J = 5.9, 3.2 Hz, 2H).
3
2
-(2-Naphthyl)-1H-benzimidazole (5l)
The spectroscopic data were in good agreement with the literature. A yellow solid. Yield: 230
1
mg (94 %). R = 0.4 (EtOAc:hexanes = 1:3). H NMR (300 MHz, DMSO-d , ppm) δ: 8.73 (s,
f
6
1
H), 8.30 (d, J = 8.5 Hz, 1H), 8.07 (d, J = 9.1 Hz, 1H), 7.97 – 8.04 (m, 2H), 7.58 – 7.62 (m,
H), 7.21 (dd, J = 5.9, 3.2 Hz, 2H).
4
3
2
-(Furan-2-yl)-1H-benzimidazole (5m)
The spectroscopic data were in good agreement with the literature. A brown solid. Yield: 166
1
mg (90 %). R = 0.4 (MeOH:CH Cl = 1:20). H NMR (300 MHz, DMSO-d , ppm) δ: 7.94 (s,
f
2
2
6
1
H), 7.55 (br, 2H), 7.16 – 7.23 (m, 3H), 6.73 (dd, J = 3.4, 1.8 Hz, 1H).
3
2
-(Thien-2-yl)-1H-benzimidazole (5n)
The spectroscopic data were in good agreement with the literature. A light yellow solid. 186
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1
mg (93 %). R = 0.5 (MeOH:CH Cl = 1:20). H NMR (300 MHz, DMSO-d , ppm) δ: 7.83 (d,
f
2
2
6
J = 3.6 Hz, 1H), 7.73(d, J = 4.9 Hz, 1H), 7.50 – 7.59 (m, 2H), 7.15 – 7.26 (m, 3H).
6
2
-(Pyrid-2-yl)-1H-benzimidazole (5o)
The spectroscopic data were in good agreement with the literature. A yellow solid. Yield: 182
1
mg (93 %). R = 0.5 (MeOH:CH Cl = 1:20). H NMR (300 MHz, CDCl , ppm) δ: 10.55 (br,
f
2
2
3
1
H), 8.65 (d, J = 4.7 Hz, 1H), 8.44 (d, J = 8.0 Hz, 1H), 7.83 – 7.92 (m, 2H), 7.48 – 7.56 (m,
1
H), 7.30 – 7.42 (m, 3H).
6
2
-trans-Cinnamyl-1H-benzimidazole (5p)
The spectroscopic data were in good agreement with the literature. A yellow oil. Yield: 152
1
mg (69 %). R = 0.4 (EtOAc:hexanes = 1:2). H NMR (300 MHz, DMSO-d , ppm) δ: 7.54 -
f
6
7
.73 (m, 4H), 7.39 - 7.50 (m, 3H), 7.36 (d, J = 6.9 Hz, 1H), 7.11 - 7.27 (m, 3H).
7
2
-Hexyl-1H-benzimidazole (5q)
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The spectroscopic data were in good agreement with the literature. A white solid. Yield: 140
1
mg (69 %). R = 0.4 (EtOAc:hexanes = 1:1). H NMR (300 MHz, DMSO-d , ppm) δ: 12.14
f
6
(br, 1H), 7.34 - 7.60 (m, 2H), 7.09 (d, J = 3.0 Hz, 2H), 2.78 (t, J = 7.4 Hz, 2H), 1.74 (br, 2H),
1
.29 (br, 6H), 0.85 (br, 3H).
8
2
-Cyclohexyl-1H-benzimidazole (5r)
The spectroscopic data were in good agreement with the literature. A white solid. Yield: 140
1
mg (70 %). R = 0.4 (EtOAc:hexanes = 1:3). H NMR (300 MHz, DMSO-d , ppm) δ: 12.09
f
6
(br, 1H), 7.31 - 7.60 (m, 2H), 6.97 - 7.22 (m, 2H), 2.83 (tt, J = 11.40, 3.57 Hz, 1H), 2.00 (d, J
=
12.64 Hz, 2H), 1.75 - 1.86 (m, 2H), 1.74 - 1.18 (m, 6H).
9
2
-(t-Butyl)-1H-benzimidazole (5s)
The spectroscopic data were in good agreement with the literature. A brown solid. Yield: 122
1
mg (70 %). R = 0.3 (EtOAc:hexanes = 1:3). H NMR (300 MHz, DMSO-d , ppm) δ: 12.06 (s,
f
6
1
H), 7.51 (d, J = 6.9 Hz, 1H), 7.39 (d, J = 7.1 Hz, 1H), 7.06 – 7.13 (m, 2H), 1.38 (s, 9H).
1
0
Benzimidazole (5t)
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The spectroscopic data were in good agreement with the literature. A white solid. Yield: 97.7
1
mg (83 %). R = 0.5 (Acetone:MeOH = 30:1). H NMR (300 MHz, DMSO-d , ppm) δ: 12.44
f
6
(br, 1H), 8.20 (s, 1H), 7.46-7.70 (m, 2H), 7.18 (br, 1H).
3
5
-Methyl-2-phenyl-1H-benzoimidazole (5u)
The spectroscopic data were in good agreement with the literature. A yellow solid. Yield: 179
1
mg (86 %). R = 0.4 (EtOAc:hexanes = 1:3). H NMR (300 MHz, DMSO-d , ppm) δ: 8.15 (d,
f
6
J = 7.1 Hz, 2H), 7.44 - 7.57 (m, 4H), 7.32 (br, 1H), 7.02 (d, J = 7.1 Hz, 1H), 2.43 (s, 3 H).
3
5
-Chloro-2-phenyl-1H-benzoimidazole (5v)
The spectroscopic data were in good agreement with the literature. A pink solid. Yield: 183
1
mg (80 %). R = 0.4 (EtOAc:hexanes = 1:3). H NMR (300 MHz, DMSO-d , ppm) δ: 8.13 -
f
6
8
.19 (m, 2H), 7.51 - 7.66 (m, 3H), 7.23 (dd, J = 8.7, 2.1 Hz, 1H).
11
2
-Phenyl-3H-benzoimidazole-5-carboxylic acid (5w)
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The spectroscopic data were in good agreement with the literature. A yellow solid. Yield: 208
1
mg (82 %). R = 0.4 (EtOAc:hexanes:MeOH = 6:5:1). H NMR (300 MHz, DMSO-d , ppm)
f
6
δ: 8.20 (d, J = 6.9 Hz, 3H), 7.84 (d, J = 8.5 Hz, 1H), 7.51 - 7.67 (m, 4H).
8
1
-Methyl-2-phenyl-1H-benzoimidazole (5x)
The spectroscopic data were in good agreement with the literature. A yellow solid. Yield: 188
1
mg (90 %). R = 0.3 (EtOAc:hexanes = 1:2). H NMR (300 MHz, DMSO-d , ppm) δ: 7.84 –
f
6
7
.87(m, 2H), 7.68 (d, J = 8.2 Hz, 1H), 7.57 – 7.63 (m, 4H), 7.22 – 7.33 (m, 2H), 3.88 (s, 3H).
1
2
1
-Benzyl-2-phenyl-1H-benzoimidazole (7a)
The spectroscopic data were in good agreement with the literature. A yellow solid. Yield: 256 mg
1
(
90 %). R = 0.4 (EtOAc:hexanes = 1:2). H NMR (300 MHz, DMSO-d , ppm) δ
:
7.71 – 7.74 (m, 3H),
f
6
7
.52 – 7.54 (m, 3H), 7.45 – 7.48 (m, 1H), 7.21 – 7.31 (m, 5H), 6.98 (d, J = 7.0 Hz, 2H), 5.59 (s, 2H).
1
3
1
,2-diphenyl-1H-benzoimidazole (5y)
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The spectroscopic data were in good agreement with the literature. A white solid. Yield: mg (90 %).
1
R = (EtOAc:hexanes =). H NMR (400 MHz, CDCl , ppm) δ
:
7.71 – 7.74 (m, 3H), 7.52 – 7.54 (m,
f
3
3
H), 7.45 – 7.48 (m, 1H), 7.21 – 7.31 (m, 5H), 6.98 (d, J = 7.0 Hz, 2H), 5.59 (s, 2H).
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1
3
. H NMR spectra of benzimidazoles 5
1
a) H NMR spectrum of 5a
1
b) H NMR spectrum of 5b
S14

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1
c) H NMR spectrum of 5c
1
d) H NMR spectrum of 5d
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1
e) H NMR spectrum of 5e
1
f) H NMR spectrum of 5f
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1
g) H NMR spectrum of 5g
1
d) H NMR Spectrum of 3d
1
13
h) H and C NMR Spectra of 3h.
1
H NMR Spectrum
1
3
C NMR Spectrum
1
h) H NMR spectrum of 5h
S17

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1
i) H NMR spectrum of 5i
1
j) H NMR spectrum of 5j
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1
k) H NMR spectrum of 5k
1
l) H NMR spectrum of 5l
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1
m) H NMR spectrum of 5m
1
n) H NMR spectrum of 5n
S20